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1
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Zhang XY, Hong LL, Ling ZQ. MUC16: clinical targets with great potential. Clin Exp Med 2024; 24:101. [PMID: 38758220 PMCID: PMC11101557 DOI: 10.1007/s10238-024-01365-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 04/29/2024] [Indexed: 05/18/2024]
Abstract
Mucin 16 (MUC16) is a membrane-bound mucin that is abnormally expressed or mutated in a variety of diseases, especially tumors, while being expressed in normal body epithelium. MUC16 and its extracellular components are often important cancer-related biomarkers. Abnormal expression of MUC16 promotes tumor progression through mesenchymal protein, PI3K/AKT pathway, JAK2/STAT3 pathway, ERK/FBW7/c-Myc, and other mechanisms, and plays an important role in the occurrence and development of tumors. In addition, MUC16 also helps tumor immune escape by inhibiting T cells and NK cells. Many drugs and trials targeting MUC16 have been developed, and MUC16 may be a new direction for future treatments. In this paper, the mechanism of action of MUC16 in the development of cancer, especially in the immune escape of tumor, is introduced in detail, indicating the potential of MUC16 in clinical treatment.
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Affiliation(s)
- Xin-Yu Zhang
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou, 310022, Zhejiang, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China
- The Second Clinical Medical College of Zhejiang, Chinese Medicine University, Hangzhou, 310053, China
| | - Lian-Lian Hong
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou, 310022, Zhejiang, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China
| | - Zhi-Qiang Ling
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou, 310022, Zhejiang, China.
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China.
- The Second Clinical Medical College of Zhejiang, Chinese Medicine University, Hangzhou, 310053, China.
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Martinez-Carrasco R, Argüeso P, Fini ME. Membrane-associated mucins of the human ocular surface in health and disease. Ocul Surf 2021; 21:313-330. [PMID: 33775913 PMCID: PMC8328898 DOI: 10.1016/j.jtos.2021.03.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/02/2021] [Accepted: 03/08/2021] [Indexed: 02/06/2023]
Abstract
Mucins are a family of high molecular weight, heavily-glycosylated proteins produced by wet epithelial tissues, including the ocular surface epithelia. Densely-packed O-linked glycan chains added post-translationally confer the biophysical properties of hydration, lubrication, anti-adhesion and repulsion. Membrane-associated mucins (MAMs) are the distinguishing components of the mucosal glycocalyx. At the ocular surface, MAMs maintain wetness, lubricate the blink, stabilize the tear film, and create a physical barrier to the outside world. In addition, it is increasingly appreciated that MAMs function as cell surface receptors that transduce information from the outside to the inside of the cell. Recently, our team published a comprehensive review/perspectives article for molecular scientists on ocular surface MAMs, including previously unpublished data and analyses on two new genes MUC21 and MUC22, as well as new MAM functions and biological roles, comparing human and mouse (PMID: 31493487). The current article is a refocus for the audience of The Ocular Surface. First, we update the gene and protein information in a more concise form, and include a new section on glycosylation. Next, we discuss biological roles, with some new sections and further updating from our previous review. Finally, we provide a new chapter on MAM involvement in ocular surface disease. We end this with discussion of an emerging mechanism responsible for damage to the epithelia and their mucosal glycocalyces: the unfolded protein response (UPR). The UPR offers a novel target for therapeutic intervention.
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Affiliation(s)
- Rafael Martinez-Carrasco
- Department of Ophthalmology, Tufts University School of Medicine at New England Eye Center, Tufts Medical Center, Boston, MA, 02111, USA.
| | - Pablo Argüeso
- Department of Ophthalmology, Harvard Medical School at Schepens Eye Research Institute of Mass, Eye and Ear, Boston, MA, 02114, USA.
| | - M Elizabeth Fini
- Department of Ophthalmology, Tufts University School of Medicine at New England Eye Center, Tufts Medical Center: Program in Pharmacology & Drug Development, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, O2111, USA.
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Giamougiannis P, Martin-Hirsch PL, Martin FL. The evolving role of MUC16 (CA125) in the transformation of ovarian cells and the progression of neoplasia. Carcinogenesis 2021; 42:327-343. [PMID: 33608706 DOI: 10.1093/carcin/bgab010] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 01/19/2021] [Accepted: 02/15/2021] [Indexed: 12/23/2022] Open
Abstract
MUC16 (the cancer antigen CA125) is the most commonly used serum biomarker in epithelial ovarian cancer, with increasing levels reflecting disease progression. It is a transmembrane glycoprotein with multiple isoforms, undergoing significant changes through the metastatic process. Aberrant glycosylation and cleavage with overexpression of a small membrane-bound fragment consist MUC16-related mechanisms that enhance malignant potential. Even MUC16 knockdown can induce an aggressive phenotype but can also increase susceptibility to chemotherapy. Variable MUC16 functions help ovarian cancer cells avoid immune cytotoxicity, survive inside ascites and form metastases. This review provides a comprehensive insight into MUC16 transformations and interactions, with description of activated oncogenic signalling pathways, and adds new elements on the role of its differential glycosylation. By following the journey of the molecule from pre-malignant states to advanced stages of disease it demonstrates its behaviour, in relation to the phenotypic shifts and progression of ovarian cancer. Additionally, it presents proposed differences of MUC16 structure in normal/benign conditions and epithelial ovarian malignancy.
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Affiliation(s)
- Panagiotis Giamougiannis
- Department of Gynaecological Oncology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK.,School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, UK
| | - Pierre L Martin-Hirsch
- Department of Gynaecological Oncology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
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Fini ME, Jeong S, Gong H, Martinez-Carrasco R, Laver NMV, Hijikata M, Keicho N, Argüeso P. Membrane-associated mucins of the ocular surface: New genes, new protein functions and new biological roles in human and mouse. Prog Retin Eye Res 2019; 75:100777. [PMID: 31493487 DOI: 10.1016/j.preteyeres.2019.100777] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 08/26/2019] [Accepted: 08/31/2019] [Indexed: 01/17/2023]
Abstract
The mucosal glycocalyx of the ocular surface constitutes the point of interaction between the tear film and the apical epithelial cells. Membrane-associated mucins (MAMs) are the defining molecules of the glycocalyx in all mucosal epithelia. Long recognized for their biophysical properties of hydration, lubrication, anti-adhesion and repulsion, MAMs maintain the wet ocular surface, lubricate the blink, stabilize the tear film and create a physical barrier to the outside world. However, it is increasingly appreciated that MAMs also function as cell surface receptors that transduce information from the outside to the inside of the cell. A number of excellent review articles have provided perspective on the field as it has progressed since 1987, when molecular cloning of the first MAM was reported. The current article provides an update for the ocular surface, placing it into the broad context of findings made in other organ systems, and including new genes, new protein functions and new biological roles. We discuss the epithelial tissue-equivalent with mucosal differentiation, the key model system making these advances possible. In addition, we make the first systematic comparison of MAMs in human and mouse, establishing the basis for using knockout mice for investigations with the complexity of an in vivo system. Lastly, we discuss findings from human genetics/genomics, which are providing clues to new MAM roles previously unimagined. Taken together, this information allows us to generate hypotheses for the next stage of investigation to expand our knowledge of MAM function in intracellular signaling and roles unique to the ocular surface.
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Affiliation(s)
- M Elizabeth Fini
- Department of Ophthalmology, Tufts University School of Medicine, at New England Eye Center, Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA.
| | - Shinwu Jeong
- USC Roski Eye Institute and Department of Ophthalmology, Keck School of Medicine of USC, University of Southern California, 1975 Zonal Ave, Los Angeles, CA, 90033, USA.
| | - Haiyan Gong
- Department of Ophthalmology, Boston University School of Medicine, 72 E Concord St, Boston, MA, 02118, USA.
| | - Rafael Martinez-Carrasco
- Department of Ophthalmology, Tufts University School of Medicine, at New England Eye Center, Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA.
| | - Nora M V Laver
- Department of Ophthalmology, Tufts University School of Medicine, at New England Eye Center, Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA.
| | - Minako Hijikata
- Department of Pathophysiology and Host Defense, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, 3-1-24 Matsuyama, Kiyose-shi, Tokyo, 204-8533, Japan.
| | - Naoto Keicho
- Department of Pathophysiology and Host Defense, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, 3-1-24 Matsuyama, Kiyose-shi, Tokyo, 204-8533, Japan.
| | - Pablo Argüeso
- Department of Ophthalmology, Harvard Medical School, at Schepens Eye Research Institute of Mass. Eye and Ear, 20 Staniford St, Boston, MA, 02114, USA.
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O'Brien TJ, Tanimoto H, Konishi I, Gee M. More than 15 Years of CA 125: What is Known about the Antigen, Its Structure and Its Function. Int J Biol Markers 2018; 13:188-95. [PMID: 10228899 DOI: 10.1177/172460089801300403] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In 1997 CA 125 celebrated its 15th anniversary. Since the discovery of OC 125, an antibody that recognizes CA 125, by Bob Bast and his colleagues, considerable progress has been made toward the development of more sensitive and more precise assay systems. However, a great deal of mystery still remains about the CA 125 molecule and further enlightenment will probably not come until the gene for CA 125 is cloned and the complete open reading frame for the peptide core identified. In the meantime, we have learned some structural features of the CA 125 molecule as well as a little about its regulation and the requirements for its secretion or release from epithelial derived cells in cultures. The CA 125 molecule is almost certainly a glycoprotein with a predominance of O-linkages. It is heterogeneous with regard to both size and charge, most likely due to continuous deglycosylation of side chains during its life-span in bodily fluids. It exists as a very large complex (perhaps as much as 4 million daltons) under natural conditions. The core CA 125 subunit is in excess of 200,000 daltons and it retains the capacity to bind both OC 125 class antibodies and M 11 class antibodies. As a denatured purified subspecies the CA 125 molecule appears to autoproteolyse presumably due to an endogenous protease activity inherent to the molecule. Release or secretion of CA 125 appears directly linked to the epithelial growth factor receptor signal transduction pathway. Prior to its release from cultured cells, CA 125 is phosphorylated (at either/both serine and threonine) and dephosphorylated when released. To stimulate discussion on the regulation of CA 125 synthesis, its secretion and its structural configuration, we have presented a model of a theoretical CA 125 molecule. Perhaps it will provide a focus of attention until the CA 125 gene is cloned and the real molecule is described.
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Affiliation(s)
- T J O'Brien
- Department of Obstetrics and Gynecology, Kyoto University, Japan
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Coelho R, Marcos-Silva L, Ricardo S, Ponte F, Costa A, Lopes JM, David L. Peritoneal dissemination of ovarian cancer: role of MUC16-mesothelin interaction and implications for treatment. Expert Rev Anticancer Ther 2017; 18:177-186. [PMID: 29241375 DOI: 10.1080/14737140.2018.1418326] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
INTRODUCTION Peritoneal dissemination is a particular form of malignant progression in ovarian cancer, preceding hematogenic or lymphatic dissemination. Thus, prevention of peritoneal implantation of cancer cells is envisioned to inhibit neoplastic dissemination and therefore prolong disease remission and patient's survival. Areas covered: An extended review on the role of MUC16 (CA125) and mesothelin (MSLN), expressed in a high percentage of ovarian carcinomas, indicate that this duet is relevant for the contact between cancer cells and mesothelial cells in homotypic (cancer cell-cancer cell) and heterotypic (cancer cell-mesothelial cell) interactions. This review discusses the reasons underlying the clinical failure of immunotherapeutic strategies targeting MUC16. Clinical data on MSLN targeting agents such as antibody-based immunotoxins or antibody drug conjugates are also reviewed. The promising anti-tumor effect of CAR-T cells directed to MUC16 or MSLN is emphasized. New emerging strategies specifically disrupting the MUC16-MSLN interaction are at the forefront of this review, including TRAIL ligands bound to MSLN targeting MUC16 expressing cells and single chain monoclonal antibodies and immunoadhesins recognizing MSLN-MUC16 binding domains. Expert commentary: Based on existing evidences the authors advocate that agents targeting MUC16-MSLN may add to the therapeutic armamentarium directed to abrogate peritoneal homing of ovarian cancer.
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Affiliation(s)
- Ricardo Coelho
- a Differentiation and Cancer Group, IPATIMUP/i3S , Institute of Molecular Pathology and Immunology of the University of Porto/Institute for Research and Innovation in Health of University of Porto , Porto , Portugal.,b FMUP , Faculty of Medicine of University of Porto , Porto , Portugal
| | - Lara Marcos-Silva
- a Differentiation and Cancer Group, IPATIMUP/i3S , Institute of Molecular Pathology and Immunology of the University of Porto/Institute for Research and Innovation in Health of University of Porto , Porto , Portugal.,c Animal Cell Technology Unit, ITQB, Instituto de Tecnologia Química e Biológica António Xavier , Universidade Nova de Lisboa, Lisboa, Portugal and iBET, Instituto de Biologia Experimental e Tecnológica , Oeiras , Portugal
| | - Sara Ricardo
- a Differentiation and Cancer Group, IPATIMUP/i3S , Institute of Molecular Pathology and Immunology of the University of Porto/Institute for Research and Innovation in Health of University of Porto , Porto , Portugal.,b FMUP , Faculty of Medicine of University of Porto , Porto , Portugal
| | - Filipa Ponte
- a Differentiation and Cancer Group, IPATIMUP/i3S , Institute of Molecular Pathology and Immunology of the University of Porto/Institute for Research and Innovation in Health of University of Porto , Porto , Portugal
| | - Antonia Costa
- b FMUP , Faculty of Medicine of University of Porto , Porto , Portugal.,d Gynecology and Obstetrics Department , Centro hospitalar de São João , Porto , Portugal.,e Monitoring and simulation of perinatal asphyxia group, INEB/i3S, Instituto de Engenharia Biomédica , Universidade do Porto, Porto, Portugal/Institute for Research and Innovation in Health of University of Porto , Porto , Portugal
| | - Jose Manuel Lopes
- b FMUP , Faculty of Medicine of University of Porto , Porto , Portugal.,f Pathology Department , Centro hospitalar de São João , Porto , Portugal.,g Cancer Cell Signalling and Metabolism Group, IPATIMUP/i3S , Institute of Molecular Pathology and Immunology of the University of Porto/Institute for Research and Innovation in Health of University of Porto , Porto , Portugal
| | - Leonor David
- a Differentiation and Cancer Group, IPATIMUP/i3S , Institute of Molecular Pathology and Immunology of the University of Porto/Institute for Research and Innovation in Health of University of Porto , Porto , Portugal.,b FMUP , Faculty of Medicine of University of Porto , Porto , Portugal
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Ohyama K, Yoshimi H, Aibara N, Nakamura Y, Miyata Y, Sakai H, Fujita F, Imaizumi Y, Chauhan AK, Kishikawa N, Kuroda N. Immune complexome analysis reveals the specific and frequent presence of immune complex antigens in lung cancer patients: A pilot study. Int J Cancer 2016; 140:370-380. [DOI: 10.1002/ijc.30455] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 09/16/2016] [Indexed: 12/29/2022]
Affiliation(s)
- Kaname Ohyama
- Course of Pharmaceutical Sciences, Graduate School of Biomedical Sciences; Nagasaki University; Nagasaki Japan
- Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (NRGIC); Nagasaki Japan
| | - Haruka Yoshimi
- Course of Pharmaceutical Sciences, Graduate School of Biomedical Sciences; Nagasaki University; Nagasaki Japan
| | - Nozomi Aibara
- Course of Pharmaceutical Sciences, Graduate School of Biomedical Sciences; Nagasaki University; Nagasaki Japan
| | - Yoichi Nakamura
- Second Department of Internal Medicine; Nagasaki University Hospital, Nagasaki University; Nagasaki Japan
| | - Yasuyoshi Miyata
- Department of Urology, Graduate School of Biomedical Sciences; Nagasaki University; Nagasaki Japan
| | - Hideki Sakai
- Department of Urology, Graduate School of Biomedical Sciences; Nagasaki University; Nagasaki Japan
| | - Fumihiko Fujita
- Department of Transplantation and Digestive Surgery, Graduate School of Biomedical Sciences; Nagasaki University; Nagasaki Japan
| | - Yoshitaka Imaizumi
- Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit; Bomb Disease Institute, Nagasaki University; Nagasaki Japan
| | - Anil K Chauhan
- Division of Adult and Pediatric Rheumatology; Saint Louis University School of Medicine; St. Louis MO
| | - Naoya Kishikawa
- Course of Pharmaceutical Sciences, Graduate School of Biomedical Sciences; Nagasaki University; Nagasaki Japan
| | - Naotaka Kuroda
- Course of Pharmaceutical Sciences, Graduate School of Biomedical Sciences; Nagasaki University; Nagasaki Japan
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8
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Ablamowicz AF, Nichols JJ. Ocular Surface Membrane-Associated Mucins. Ocul Surf 2016; 14:331-41. [PMID: 27154035 DOI: 10.1016/j.jtos.2016.03.003] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 03/29/2016] [Accepted: 03/01/2016] [Indexed: 01/17/2023]
Abstract
Ocular surface epithelial cells produce and secrete mucins that form a hydrophilic barrier for protection and lubrication of the eye. This barrier, the glycocalyx, is formed by high molecular weight heavily glycosylated membrane-associated mucins (MAMs) that include MUC1, MUC4, and MUC16. These mucins extend into the tear film from the anterior surfaces of the conjunctiva and cornea, and, through interactions with galectin-3, prevent penetrance of pathogens into the eye. Due primarily to the glycosylation of the mucins, the glycocalyx also creates less friction during blinking and enables the tear film to maintain wetting of the eye. The secretory mucins include soluble MUC7 and gel-forming MUC5AC. These mucins, particularly MUC5AC, assist with removal of debris from the tear film and contribute to the hydrophilicity of the tear film. While new methodologies and cell culture models have expanded our understanding of mucin structure and function on the ocular surface, there is still a paucity of studies characterizing the glycosylation of MAMs on a normal ocular surface and a diseased ocular surface. Although studies have shown alterations in mucin production and expression in dry eye diseases, the relationship between changes in mucins and functional consequences is unclear. This review focuses on comparing what is known about MAMs in wet-surfaced epithelia of the body to what has been studied on the eye.
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Affiliation(s)
- Anna F Ablamowicz
- School of Optometry, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jason J Nichols
- School of Optometry, University of Alabama at Birmingham, Birmingham, AL, USA.
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Piché A. Pathobiological role of MUC16 mucin (CA125) in ovarian cancer: Much more than a tumor biomarker. World J Obstet Gynecol 2016; 5:39-49. [DOI: 10.5317/wjog.v5.i1.39] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/11/2015] [Accepted: 12/11/2015] [Indexed: 02/05/2023] Open
Abstract
MUC16 (CA125) has remained the mainstay for ovarian cancer assessment and management since the early 1980’s. With the exception of HE4, it is the only reliable serum biomarker for ovarian cancer. MUC16 belongs to a family of high-molecular weight glycoproteins known as mucins. The mucin family is comprised of large secreted transmembrane proteins that includes MUC1, MUC4 and MUC16. These mucins are often overexpressed in a variety of malignancies. MUC1 and MUC4 have been shown to contribute to breast and pancreatic tumorigenesis. Recent studies have uncovered unique biological functions for MUC16 that go beyond its role as a biomarker for ovarian cancer. Here, we provide an overview of the literature to highlight the importance of MUC16 in ovarian cancer tumorigenesis. We focus on the growing literature describing the role of MUC16 in proliferation, migration, metastasis, tumorigenesis and drug resistance. Accumulating experimental evidence suggest that the C-terminal domain of MUC16 is critical to mediate theses effects. The importance of MUC16 in the pathogenesis of ovarian cancer emphasizes the need to fully understand the signaling capabilities of MUC16 C-terminal domain to develop more efficient strategies for the successful treatment of ovarian cancer.
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Das S, Batra SK. Understanding the Unique Attributes of MUC16 (CA125): Potential Implications in Targeted Therapy. Cancer Res 2015; 75:4669-74. [PMID: 26527287 DOI: 10.1158/0008-5472.can-15-1050] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 07/20/2015] [Indexed: 01/01/2023]
Abstract
CA125, the most widely used ovarian cancer biomarker, was first identified approximately 35 years ago in an antibody screen against ovarian cancer antigen. Two decades later, it was cloned and characterized to be a transmembrane mucin, MUC16. Since then, several studies have investigated its expression, functional, and mechanistic involvement in multiple cancer types. Antibody-based therapeutic approaches primarily using antibodies against the tandem repeat domains of MUC16 (e.g., oregovomab and abagovomab) have been the modus operandi for MUC16-targeted therapy, but have met with very limited success. In addition, efforts have been also made to disrupt the functional cooperation of MUC16 and its interacting partners; for example, use of a novel immunoadhesin HN125 to interfere MUC16 binding to mesothelin. Since the identification of CA125 to be MUC16, it is hypothesized to undergo proteolytic cleavage, a process that is considered to be critical in determining the kinetics of MUC16 shedding as well as generation of a cell-associated carboxyl-terminal fragment with potential oncogenic functions. In addition to our experimental demonstration of MUC16 cleavage, recent studies have demonstrated the functional importance of carboxyl terminal fragments of MUC16 in multiple tumor types. Here, we provide how our understanding of the basic biologic processes involving MUC16 influences our approach toward MUC16-targeted therapy.
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Affiliation(s)
- Srustidhar Das
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska. Department of Pathology, University of Nebraska Medical Center, Omaha, Nebraska. Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.
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12
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Das S, Majhi PD, Al-Mugotir MH, Rachagani S, Sorgen P, Batra SK. Membrane proximal ectodomain cleavage of MUC16 occurs in the acidifying Golgi/post-Golgi compartments. Sci Rep 2015; 5:9759. [PMID: 26044153 PMCID: PMC4456727 DOI: 10.1038/srep09759] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 03/13/2015] [Indexed: 12/29/2022] Open
Abstract
MUC16, precursor of the most widely used ovarian cancer biomarker CA125, is up
regulated in multiple malignancies and is associated with poor prognosis. While the
pro-tumorigenic and metastatic roles of MUC16 are ascribed to the cell-associated
carboxyl-terminal MUC16 (MUC16-Cter), the exact biochemical nature of MUC16 cleavage
generating MUC16-Cter has remained unknown. Using different lengths of dual-epitope
(N-terminal FLAG- and C-terminal HA-Tag) tagged C-terminal MUC16 fragments, we
demonstrate that MUC16 cleavage takes place in the juxta-membrane ectodomain stretch
of twelve amino acids that generates a ~17 kDa cleaved product and is
distinct from the predicted sites. This was further corroborated by domain swapping
experiment. Further, the cleavage of MUC16 was found to take place in the
Golgi/post-Golgi compartments and is dependent on the acidic pH in the secretory
pathway. A similar pattern of ~17 kDa cleaved MUC16 was observed in
multiple cell types eliminating the possibility of cell type specific phenomenon.
MUC16-Cter translocates to the nucleus in a cleavage dependent manner and binds to
the chromatin suggesting its involvement in regulation of gene expression. Taken
together, we demonstrate for the first time the oft-predicted cleavage of MUC16 that
is critical in designing successful therapeutic interventions based on MUC16.
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Affiliation(s)
- Srustidhar Das
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Prabin D Majhi
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Mona H Al-Mugotir
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Paul Sorgen
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Surinder K Batra
- 1] Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA [2] Department of Pathology, University of Nebraska Medical Center, Omaha, NE 68198, USA [3] Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
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13
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Giannakouros P, Matte I, Rancourt C, Piché A. Transformation of NIH3T3 mouse fibroblast cells by MUC16 mucin (CA125) is driven by its cytoplasmic tail. Int J Oncol 2014; 46:91-8. [PMID: 25338620 DOI: 10.3892/ijo.2014.2707] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Accepted: 06/26/2014] [Indexed: 11/06/2022] Open
Abstract
MUC16 (CA125) is a transmembrane mucin that contributes to the progression of epithelial ovarian cancer (EOC). Expression of MUC16 is not detectable in the epithelial surface of normal ovaries. MUC16 expression is, however, common in serous EOC as well as in metastatic and recurrent tumors. Despite these observations, its contribution to the development of EOC is unknown. We stably expressed either empty vector, MUC16 C-terminal domain (MUC16 CTD) or MUC16 TMU (a construct that lacks the cytoplasmic tail) in NIH3T3 mouse fibroblast cells. In this study, we provide evidence for the role of MUC16 CTD in oncogenic transformation. We show that ectopic expression of MUC16 CTD enhances the growth of NIH3T3 cells under normal and low serum conditions, and promotes anchorage-dependent colony formation. The deletion of the cytoplasmic tail abrogated these effects. MUC16 CTD expression in NIH3T3 cells also enhances the formation of colony in soft agar as compared to MUC16 TMU. MUC16 CTD expression enhances tumor formation in nude mice. Our findings provide the first evidence that MUC16 induces the transformation of NIH3T3 cells and indicate that MUC16 functions as an oncogene. Furthermore, our data suggest that the cytoplasmic tail is critical for MUC16 oncogenic properties.
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Affiliation(s)
- Panagiota Giannakouros
- Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Isabelle Matte
- Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Claudine Rancourt
- Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Alain Piché
- Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
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Haridas D, Ponnusamy MP, Chugh S, Lakshmanan I, Seshacharyulu P, Batra SK. MUC16: molecular analysis and its functional implications in benign and malignant conditions. FASEB J 2014; 28:4183-4199. [PMID: 25002120 DOI: 10.1096/fj.14-257352] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
MUC16 is a high-molecular-weight glycoprotein that is expressed by the various epithelial cell surfaces of the human body to protect the cell layer from a myriad of insults. It is the largest mucin known to date, with an ∼22,152 aa sequence. Structurally, MUC16 is characterized into 3 distinct domains: the amino terminal, the tandem repeat, and the carboxyl terminal domain, with each domain having unique attributes. The extracellular portion of MUC16 is shed into the bloodstream and serves as a biomarker for diagnosing and monitoring patients with cancer; however, its functional role in cancer is yet to be elucidated. Several factors contribute to this challenge, which include the large protein size; the extensive glycosylation that the protein undergoes, which confers functional heterogeneity; lack of specific antibodies that detect the unique domains of MUC16; and the existence of splicing variants. Despite these limitations, MUC16 has been established as a molecule of significant application in cancer. Hence, in this review, we discuss the various aspects of MUC16, which include its discovery, structure, and biological significance both in benign and malignant conditions with an attempt to dissect its functional relevance
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Affiliation(s)
| | | | - Seema Chugh
- Department of Biochemistry and Molecular Biology
| | | | | | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
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15
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Felder M, Kapur A, Gonzalez-Bosquet J, Horibata S, Heintz J, Albrecht R, Fass L, Kaur J, Hu K, Shojaei H, Whelan RJ, Patankar MS. MUC16 (CA125): tumor biomarker to cancer therapy, a work in progress. Mol Cancer 2014; 13:129. [PMID: 24886523 PMCID: PMC4046138 DOI: 10.1186/1476-4598-13-129] [Citation(s) in RCA: 348] [Impact Index Per Article: 31.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Accepted: 05/13/2014] [Indexed: 12/21/2022] Open
Abstract
Over three decades have passed since the first report on the expression of CA125 by ovarian tumors. Since that time our understanding of ovarian cancer biology has changed significantly to the point that these tumors are now classified based on molecular phenotype and not purely on histological attributes. However, CA125 continues to be, with the recent exception of HE4, the only clinically reliable diagnostic marker for ovarian cancer. Many large-scale clinical trials have been conducted or are underway to determine potential use of serum CA125 levels as a screening modality or to distinguish between benign and malignant pelvic masses. CA125 is a peptide epitope of a 3-5 million Da mucin, MUC16. Here we provide an in-depth review of the literature to highlight the importance of CA125 as a prognostic and diagnostic marker for ovarian cancer. We focus on the increasing body of literature describing the biological role of MUC16 in the progression and metastasis of ovarian tumors. Finally, we consider previous and on-going efforts to develop therapeutic approaches to eradicate ovarian tumors by targeting MUC16. Even though CA125 is a crucial marker for ovarian cancer, the exact structural definition of this antigen continues to be elusive. The importance of MUC16/CA125 in the diagnosis, progression and therapy of ovarian cancer warrants the need for in-depth research on the biochemistry and biology of this mucin. A renewed focus on MUC16 is likely to culminate in novel and more efficient strategies for the detection and treatment of ovarian cancer.
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Affiliation(s)
- Mildred Felder
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Arvinder Kapur
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | | | - Sachi Horibata
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Joseph Heintz
- Department of Animal Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Ralph Albrecht
- Department of Animal Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Lucas Fass
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Justanjyot Kaur
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Kevin Hu
- Department of Chemistry and Biochemistry, Oberlin College, Oberlin, OH 44074, USA
| | - Hadi Shojaei
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Rebecca J Whelan
- Department of Chemistry and Biochemistry, Oberlin College, Oberlin, OH 44074, USA
| | - Manish S Patankar
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53792, USA
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Akita K, Tanaka M, Tanida S, Mori Y, Toda M, Nakada H. CA125/MUC16 interacts with Src family kinases, and over-expression of its C-terminal fragment in human epithelial cancer cells reduces cell-cell adhesion. Eur J Cell Biol 2013; 92:257-63. [PMID: 24246580 DOI: 10.1016/j.ejcb.2013.10.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Revised: 09/02/2013] [Accepted: 10/07/2013] [Indexed: 11/19/2022] Open
Abstract
MUC16/CA125 is over-expressed in human epithelial tumors including ovarian, breast and some other carcinomas. The purpose of this study is to investigate how cell surface MUC16 is functionally involved in tumor progression, with a special focus on the role of its cytoplasmic tail. Forced expression of C-terminal MUC16 fragment (MUC16C) in epithelial cancer cells increased cell migration. We found that MUC16C directly interacted with Src family kinases (SFKs). Notably, localizations of E-cadherin and β-catenin at the cell-cell contacts were more diffuse in MUC16C transfectants compared with mock transfectants. Furthermore, MUC16C transfectants showed reduced Ca(2+)-dependent cell-cell adhesion, but the treatment of cells with PP2, a SFKs inhibitor, restored this. Because cell surface MUC16 is also associated with the E-cadherin/β-catenin complex, the over-expression of MUC16 and its interaction with SFKs may enhance SFKs-induced deregulation of E-cadherin. Thus, our results suggest a role for cell surface MUC16 in cell-cell adhesion of epithelial cancer cells.
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Affiliation(s)
- Kaoru Akita
- Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-Motoyama, Kita-ku, Kyoto 603-8555, Japan.
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17
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MUC16 induced rapid G2/M transition via interactions with JAK2 for increased proliferation and anti-apoptosis in breast cancer cells. Oncogene 2011; 31:805-17. [PMID: 21785467 DOI: 10.1038/onc.2011.297] [Citation(s) in RCA: 112] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
MUC16/CA125 is a tumor marker currently used in clinics for the follow-up of patients with ovarian cancer. However, MUC16 expression is not entirely restricted to ovarian malignancies and has been reported in other cancers including breast cancer. Although it is well established as a biomarker, function of MUC16 in cancer remains to be elucidated. In the present study, we investigated the role of MUC16 in breast cancer and its underlying mechanisms. Interestingly, our results showed that MUC16 is overexpressed in breast cancer tissues whereas not expressed in non-neoplastic ducts. Further, stable knockdown of MUC16 in breast cancer cells (MDA MB 231 and HBL100) resulted in significant decrease in the rate of cell growth, tumorigenicity and increased apoptosis. In search of a mechanism for breast cancer cell proliferation we found that MUC16 interacts with the ezrin/radixin/moesin domain-containing protein of Janus kinase (JAK2) as demonstrated by the reciprocal immunoprecipitation method. These interactions mediate phosphorylation of STAT3 (Tyr705), which might be a potential mechanism for MUC16-induced proliferation of breast cancer cells by a subsequent co-transactivation of transcription factor c-Jun. Furthermore, silencing of MUC16 induced G2/M arrest in breast cancer cells through downregulation of Cyclin B1 and decreased phosphorylation of Aurora kinase A. This in turn led to enhanced apoptosis in the MUC16-knockdown breast cancer cells through Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated extrinsic apoptotic pathway with the help of c-Jun N-terminal kinase signaling. Collectively, our results suggest that MUC16 has a dual role in breast cancer cell proliferation by interacting with JAK2 and by inhibiting the apoptotic process through downregulation of TRAIL.
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18
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Novel monoclonal antibodies against the proximal (carboxy-terminal) portions of MUC16. Appl Immunohistochem Mol Morphol 2011; 18:462-72. [PMID: 20453816 DOI: 10.1097/pai.0b013e3181dbfcd2] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The CA125 antigen, recognized by the OC125 antibody, is a tissue-specific circulating antigen expressed in ovarian cancer. The CA125 antigen is encoded by the MUC16 gene cloned by Yin and Lloyd. The full-length gene describes a complex tethered mucin protein present primarily in a variety of gynecologic tissues, especially neoplasms. OC125 and other related antibodies react with glycosylation-dependent antigens present exclusively in the cleaved portion of the molecule. These antibodies are not useful as screening tools, nor can they detect the proximal residual MUC16 protein fragment after cleavage. This has limited its diagnostic and therapeutic applications. Using synthetic peptides, we raised novel-specific antibodies to the carboxy-terminal portion of MUC16 retained by the cell proximal to the putative cleavage site. These antibodies were characterized using fluorescence-activated cell-sorting analysis, enzyme-linked immunoassay, Western blot analysis, and immunohistochemistry. Each of the selected monoclonal antibodies was reactive against recombinant GST-ΔMUC16 protein and the MUC16-transfected SKOV3 cell line. Three antibodies, 4H11, 9C9, and 4A5 antibodies showed high affinities by Western blot analysis and saturation-binding studies of transfected-SKOV3 cells and displayed antibody internalization. Immunohistochemical positivity with novel antibody 4H11 was similar to OC125 but with important differences, including diffuse positivity in lobular breast cancer and a small percentage of OC125-negative ovarian carcinomas that showed intense and diffuse 4H11. Development of such antibodies may be useful for the characterization of MUC16 biology and allow for future studies in targeted therapy and diagnostics.
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Pfisterer J, Harter P, Simonelli C, Peters M, Berek J, Sabbatini P, du Bois A. Abagovomab for ovarian cancer. Expert Opin Biol Ther 2011; 11:395-403. [DOI: 10.1517/14712598.2011.553598] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Govindarajan B, Gipson IK. Membrane-tethered mucins have multiple functions on the ocular surface. Exp Eye Res 2010; 90:655-63. [PMID: 20223235 PMCID: PMC2893012 DOI: 10.1016/j.exer.2010.02.014] [Citation(s) in RCA: 159] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2010] [Revised: 02/24/2010] [Accepted: 02/26/2010] [Indexed: 11/30/2022]
Abstract
Membrane-tethered mucins are large glycoproteins present in the glycocalyx along the apical surface of all wet-surfaced epithelia of the body, including that of the ocular surface. Originally thought to function only in epithelial surface lubrication and hydration, data now indicate that the mucins are multifunctional molecules, each having unique as well as common functions. This review summarizes current knowledge regarding the three major membrane mucins of the ocular surface, MUC1, MUC4, and MUC16. The mucins vary in their ocular surface distribution, size, structural motifs, and functions. The ectodomains of each are released into the tear film and are, thus, a component of the soluble mucins of the tear film. Both animal and in vitro models for their study are herein described, as are alterations of the mucins in ocular surface disease.
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Affiliation(s)
- Bharathi Govindarajan
- Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Ilene K. Gipson
- Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
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21
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Abstract
Cell surface mucins are large transmembrane glycoproteins involved in diverse functions ranging from shielding the airway epithelium against pathogenic infection to regulating cellular signaling and transcription. Although hampered by the relatively recent characterization of cell surface mucins and the difficulties inherent in working with molecules of their size, numerous studies have placed the tethered mucins in the thick of normal and diseased lung physiology. This review focuses on the three best-characterized cell surface mucins expressed in the respiratory tract: MUC1, MUC4, and MUC16.
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Affiliation(s)
- Christine L Hattrup
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AR 85259, USA
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22
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Canevari S, Gariboldi M, Reid JF, Bongarzone I, Pierotti MA. Molecular predictors of response and outcome in ovarian cancer. Crit Rev Oncol Hematol 2006; 60:19-37. [PMID: 16829123 DOI: 10.1016/j.critrevonc.2006.03.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2005] [Revised: 03/30/2006] [Accepted: 03/30/2006] [Indexed: 02/03/2023] Open
Abstract
A major problem in clinical management of patients with epithelial ovarian cancer (EOC) is the largely unpredictable response to first-line treatment and the occurrence of relapse after complete initial response, associated with broad cross-resistance to even structurally dissimilar drugs. During tumor development and progression, multiple genic alterations take place that might contribute specifically to the treatment response and eventually impact on disease outcome. One area of intense research is the identification of molecular markers to accurately assess the prognosis of EOC patients and to define innovative therapeutic strategies. A large survey of recent published data indicates the need to revisit traditional molecular markers with respect to their contribution to the assessment of overall survival in selected populations. Furthermore, recent technological developments that enable simultaneous measurement of many parameters ("omic" approaches) hold the promise of identifying new molecular prognostic and predictive markers.
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Affiliation(s)
- Silvana Canevari
- Unit of Molecular Therapies, Department of Experimental Oncology, Istituto Nazionale Tumori, 20133-Milan, Italy.
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23
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Scholler N, Garvik B, Hayden-Ledbetter M, Kline T, Urban N. Development of a CA125-mesothelin cell adhesion assay as a screening tool for biologics discovery. Cancer Lett 2006; 247:130-6. [PMID: 16677756 PMCID: PMC2734268 DOI: 10.1016/j.canlet.2006.03.029] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2005] [Revised: 03/21/2006] [Accepted: 03/28/2006] [Indexed: 01/10/2023]
Abstract
Preventing peritoneal implantation of ovarian carcinoma cells could prolong patient remission and survival. CA125 is expressed on most ovarian cancer cells and was reported to be a ligand of mesothelin, a peritoneal protein. We developed a cell adhesion assay with CA125-expresser ovarian cancer cells and human mesothelin-transfected cells and we confirmed that CA125 and mesothelin mediate cell attachment. We also showed that this assay supplies a high-throughput screening system for reagents able to block CA125/mesothelin-dependent cell attachment with a sensitive quantitative readout. We finally demonstrated that a mesothelin chimeric protein and anti-CA125 antibodies block CA125/mesothelin-dependent cell attachment.
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Affiliation(s)
- Nathalie Scholler
- Molecular Diagnostics Program, Public Health Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109-1024, USA.
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24
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Elola MT, Chiesa ME, Alberti AF, Mordoh J, Fink NE. Galectin-1 receptors in different cell types. J Biomed Sci 2005; 12:13-29. [PMID: 15864736 DOI: 10.1007/s11373-004-8169-5] [Citation(s) in RCA: 103] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2004] [Accepted: 09/07/2004] [Indexed: 02/07/2023] Open
Abstract
Galectins are a family of animal lectins defined by two properties: shared amino acid sequences in their carbohydrate-recognizing domain, and beta-galactoside affinity. A wide variety of biological phenomena are related to galectins, i.e., development, differentiation, morphogenesis, tumor metastasis, apoptosis, RNA splicing, and immunoregulatory function. In this review, we will focus on galectin-1 receptors, and some of the mechanisms by which this lectin affects different cell types. Several galectin-1 receptors are discussed such as CD45, CD7, CD43, CD2, CD3, CD4, CD107, CEA, actin, extracellular matrix proteins such as laminin and fibronectin, glycosaminoglycans, integrins, a beta-lactosamine glycolipid, GM1 ganglioside, polypeptide HBGp82, glycoprotein 90 K/MAC-2BP, CA125 cancer antigen, and pre-B cell receptor.
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Affiliation(s)
- María T Elola
- Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires, Patricias Argentinas, 435 (1405), Buenos Aires, Argentina.
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25
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Jankovic MM, Tapuskovic BS. Molecular forms and microheterogeneity of the oligosaccharide chains of pregnancy-associated CA125 antigen. Hum Reprod 2005; 20:2632-8. [PMID: 15905287 DOI: 10.1093/humrep/dei095] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The cancer antigen CA125 has a very complex molecular architecture in terms of both protein backbone and oligosaccharide chains. In this study, we examined the molecular forms and microheterogeneity of oligosaccharide chains of pregnancy-associated CA125, as a first step towards gaining an insight into its possible involvement as a ligand in carbohydrate-dependent interactions. The glycobiochemical properties of CA125 may be of diagnostic and biomedical importance as specific markers of physiological and pathological conditions of early pregnancy, as well as targets in different therapeutic procedures. METHODS Pregnancy-associated CA125 was characterized by gel filtration and ion-exchange chromatography, followed by lectin-affinity chromatography with a panel of plant lectins as ligands. RESULTS CA125 antigen isolated from first trimester placental extract was found to be heterogeneous in respect to molecular mass and the existence of different glyco-isoforms. Thus, elution profiles from the lectin-affinity columns demonstrated molecular subpopulations bound with low, intermediate and high affinity. Under the applied experimental conditions, CA125 bound most strongly to Triticum vulgaris agglutinin (WGA) and Ricinus communis agglutinin (RCA), but low affinity interactions occurred with the other lectins tested. CONCLUSIONS The assessment of the carbohydrate composition of N- and O-glycans of pregnancy-associated CA125 was in general agreement with available data on CA125 of cancer origin. The main difference was observed in reactivity to Canavalia ensiformis agglutinin (ConA) and Phaseolus vulgaris erythroagglutinin (PHA-E) binding.
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Affiliation(s)
- Miroslava M Jankovic
- Institute for the Application of Nuclear Energy - INEP, Belgrade, Zemun-Belgrade, Serbia and Montenegro.
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26
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McLemore MR, Aouizerat B. Introducing the MUC16 gene: implications for prevention and early detection in epithelial ovarian cancer. Biol Res Nurs 2005; 6:262-7. [PMID: 15788735 DOI: 10.1177/1099800404274445] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
More than 24,000 women in the United States are diagnosed with ovarian cancer every year, and half of these women die from their disease. Stage 1 ovarian cancer is curable in 95% of cases; however, due to inadequate screening tools and lack of symptoms in early disease, ovarian cancer is generally at Stage 3 or 4 when finally diagnosed. CA125 is a tumor antigen used to monitor the progression and regression of epithelial ovarian cancer. When its levels are elevated postsurgery (hysterectomy/salpingo-oophorectomy with or without peritoneal washings and lymph node biopsy) and postchemotherapy, it is suggestive of recurrent disease. Due to its similarly elevated levels in some nonmalignant conditions, however, it is not specific enough to be used for population screening. The CA125 molecule is considered a very large glycoprotein because of its molecular weight, and it has three domains: the carboxy terminal domain, the extracellular domain, and the amino terminal domain. MUC16 is the gene that encodes the peptide moiety of the CA125 molecule. MUC16 domains provide novel opportunities to develop new assays and refine current tools to improve the sensitivity and specificity of CA125 for population-based screening guidelines.
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Affiliation(s)
- Monica R McLemore
- University of California, 520 Frederick Street, #31, San Francisco, CA 94117, USA.
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27
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Seelenmeyer C, Wegehingel S, Lechner J, Nickel W. The cancer antigen CA125 represents a novel counter receptor for galectin-1. J Cell Sci 2003; 116:1305-18. [PMID: 12615972 DOI: 10.1242/jcs.00312] [Citation(s) in RCA: 114] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
CA125 is an ovarian cancer antigen whose recently elucidated primary structure suggests that CA125 is a giant mucin-like glycoprotein present on the cell surface of tumor cells. Here, we establish a functional link between CA125 and beta-galactoside-binding, cell-surface lectins, which are components of the extracellular matrix implicated in the regulation of cell adhesion, apoptosis, cell proliferation and tumor progression. On the basis of mass spectrometry and immunological analyses, we find that CA125 is a counter receptor for galectin-1, as both soluble and membrane-associated fragments of CA125 derived from HeLa cell lysates are shown to bind specifically to human galectin-1 with high efficiency. This interaction is demonstrated (1) to depend on beta-galactose-terminated, O-linked oligosaccharide chains of CA125, (2) to be preferential for galectin-1 versus galectin-3 and (3) to be regulated by the cellular background in which CA125 is expressed. Despite lacking a conventional signal peptide, a CA125 C-terminal fragment of 1148 amino acids, representing less than 10% of the full-length protein, retains the ability to integrate into secretory membranes such as the endoplasmic reticulum (ER) and the Golgi, and is targeted to the plasma membrane by conventional secretory transport. As demonstrated by a novel assay that reconstitutes non-conventional secretion of galectin-1 based on fluorescence-activated cell sorting (FACS), we find that tumor-derived HeLa cells expressing endogenous CA125 present more than ten times as much galectin-1 on their surface compared with non-tumor-derived, CA125-deficient CHO cells. Intriguingly, both the galectin-1 expression level and the cell-surface binding capacity for galectin-1 are shown to be similar in CHO and HeLa cells, suggesting that CA125 might be a factor involved in the regulation of galectin-1 export to the cell surface.
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Affiliation(s)
- Claudia Seelenmeyer
- Biochemie-Zentrum Heidelberg , Im Neuenheimer Feld 328, 69120 Heidelberg, Germany
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28
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Whitehouse C, Solomon E. Current status of the molecular characterization of the ovarian cancer antigen CA125 and implications for its use in clinical screening. Gynecol Oncol 2003; 88:S152-7. [PMID: 12586109 DOI: 10.1006/gyno.2002.6708] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Caroline Whitehouse
- Cancer Genetics Laboratory, Division of Medical and Molecular Genetics, GKT School of Medicine, Guy's Hospital, London
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Abstract
CA125 is an ovarian cancer antigen that is the basis for a widely used serum assay for the monitoring of patients with ovarian cancer; however, detailed information on its biochemical and molecular nature is lacking. We now report the isolation of a long, but partial, cDNA that corresponds to the CA125 antigen. A rabbit polyclonal antibody produced to purified CA125 antigen was used to screen a lambdaZAP cDNA library from OVCAR-3 cells in Escherichia coli. The longest insert from the 54 positive isolated clones had a 5797-base pair sequence containing a stop codon and a poly(A) sequence but no clear 5' initiation sequence. The deduced amino acid sequence has many of the attributes of a mucin molecule and was designated CA125/MUC16 (gene MUC16). These features include a high serine, threonine, and proline content in an N-terminal region of nine partially conserved tandem repeats (156 amino acids each) and a C-terminal region non-tandem repeat sequence containing a possible transmembrane region and a potential tyrosine phosphorylation site. Northern blotting showed that the level of MUC16 mRNA correlated with the expression of CA125 in a panel of cell lines. The molecular cloning of the CA125 antigen will lead to a better understanding of its role in ovarian cancer.
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Affiliation(s)
- B W Yin
- Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
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30
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Verheijen RH, von Mensdorff-Pouilly S, van Kamp GJ, Kenemans P. CA 125: fundamental and clinical aspects. Semin Cancer Biol 1999; 9:117-24. [PMID: 10202133 DOI: 10.1006/scbi.1998.0114] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Since the OC 125 monoclonal antibody (Mab) was generated, other Mabs to the CA 125 glycoprotein have been produced and classified into two families associated with two major epitope regions on the CA 125 molecule. New generation assays, combining Mabs to two distinct regions of the molecule, compare favorably with that of the original assays as demonstrated by ROC curves. The original CA 125 assay suffered from interference of HAMA, an important drawback considering the increasing use of murine antibodies for immunodiagnosis and treatment of ovarian cancer. This problem has been solved for the majority of currently available tests. The sensitivity of the assays for early ovarian cancer remains low, precluding its indiscriminate use for screening and diagnosis of ovarian cancer. Its use in screening for early cancer, combined with ultrasonography, is limited to high risk populations, such as women from families with mutations in the BRCA1 or 2 gene. Although CA 125 assessment may play a limited role in the (early) detection of ovarian cancer, its role in the follow-up during and after therapy is well established. The major contribution of CA 125 is in the monitoring of tumor response to chemotherapy, where it is valuable in detecting those patients with an inadequate response to the chosen treatment. The role of CA 125 in early detection of recurrences remains to be established and is currently the subject of two large clinical trials.
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Affiliation(s)
- R H Verheijen
- Department of Obstetrics and Gynaecology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands
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